Calcium-dependent regulation of neuronal excitability is rescued in Fragile X Syndrome by a tat-conjugated N-terminal fragment of FMRP
Bibliographic record
Abstract
Abstract Fragile X Syndrome arises from the loss of Fragile X Messenger Ribonucleoprotein (FMRP) needed for normal neuronal excitability and circuit functions. Recent work revealed that FMRP contributes to mossy fiber LTP by adjusting Kv4 A-type current availability through interactions with a Cav3-Kv4 ion channel complex, yet the mechanism has not yet been defined. In this study using wild-type and Fmr1 knockout (KO) tsA-201 cells and cerebellar sections from Fmr1 KO mice, we show that FMRP associates with all subunits of the Cav3.1-Kv4.3-KChIP3 complex, and is critical to enabling calcium-dependent shifts in Kv4.3 inactivation to modulate A-type current. Specifically, upon depolarization Cav3 calcium influx activates dual specific phosphatase 1/6 (DUSP1/6) to deactivate ERK1/2 (ERK) and lower phosphorylation of Kv4.3, a signalling pathway that does not function in Fmr1 KO cells. In Fmr1 KO mouse tissue slices cerebellar granule cells exhibit a hyperexcitable response to membrane depolarizations. Either incubating Fmr1 KO cells or in vivo administration of a tat-conjugated FMRP N-terminus fragment (FMRP-N-tat) rescued Cav3-Kv4 function and granule cell excitability, with a decrease in the level of DUSP6. Together these data reveal a Cav3-activated DUSP signalling pathway critical to the function of a FMRP-Cav3-Kv4 complex that is misregulated in Fmr1 KO conditions. Moreover, FMRP-N-tat restores function of this complex to rescue calcium-dependent control of neuronal excitability as a potential therapeutic approach to alleviating the symptoms of Fragile X Syndrome. Significance Statement Changes in neuronal excitability and ion channel functions have been a focus in studies of Fragile X Syndrome. Previous work identified ion channels that are regulated by FMRP through either protein translation or direct protein-protein interactions. The current study reveals FMRP as a constitutive member of a Cav3-Kv4 complex that is required for a Cav3-DUSP-ERK signalling pathway to increase A-type current and reduce cerebellar granule cell excitability. In Fmr1 KO cells, Cav3-Kv4 function and calcium-dependent modulation of A-type current is lost, leading to a hyperexcitable state of cerebellar granule cells. Pretreating with FMRP-N-tat restores all Cav3-Kv4 function and granule cell excitability, providing support for FMRP-tat peptide treatment as a potential therapeutic strategy for Fragile X Syndrome.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".